Chemical compounds

ABSTRACT

The present invention provides compounds of formula (I): 
                         
wherein
     each R independently represents a halogen atom or a C 1-4  alkyl group;   R 1  represents a C 1-4  alkyl group;   R 2  represents hydrogen or a C 1-4  alkyl group;   R 3  represents hydrogen or C 1-4  alkyl group;   R 4  represents a trifluoromethyl group;   R 5  represents hydrogen, a C 1-4  alkyl group or C(O)R 6 ;   R 6  represents C 1-4  alkyl, C 3-7  cycloalkyl, NH(C 1-4  alkyl) or N(C 1-4 alkyl) 2 ;   m is zero or an integer from 1 to 3;   n is an integer from 1 to 3;
 
or a pharmaceutically acceptable salt or solvate thereof; compositions containing the same, processes for their preparation and methods for their use in the treatment of conditions mediated by tachykinins.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/398,264, filed 29 Jul. 2003, which is a 371 Application ofPCT/GB01/04580, filed 12 Oct. 2001, which claims priority to GBApplication Ser. No. 0025354.2, filed 17 Oct. 2000.

BACKGROUND OF THE INVENTION

The present invention relates to piperidine derivatives, to processesfor their preparation, to pharmaceutical compositions containing themand to their medical use.

In particular the invention relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

WO 97/16440 describes 1-(1,2-disubstituted piperidinyl)-4-substitutedpiperazine derivatives of general formula

wherein n and m are inter alia 1, p is 1; Q is inter alia oxygen; X is acovalent bond or a bivalent radical of formula —O—, —S—, NR³; R³ ishydrogen or a C₁₋₆ alkyl group; R¹ is inter alia Ar¹; R² may be interalia Ar²C₁₋₆alkyl wherein Ar² and Ar¹ are inter alia a phenyl groupwhich may be substituted with 1, 2 or 3 substituents each independentlyselected from halo, C₁₋₄alkyl, haloC₁₋₄ alkyl, L may be inter aliahydrogen, C₁₋₆ alkyl or L is a radical of formula —CHR⁴)rC(O)Y¹R⁷,wherein r is 0, 1, 2, 3 or 4, Y¹ is inter alia a NH or a N(C₁₋₆alkyl)group or Y¹ is a covalent bond and R⁷ is inter alia C₁₋₆ alkyl or C₃₋₇cycloalkyl. The compounds are antagonists of tachykinins.

We have now found a particular class of compounds which is notspecifically disclosed therein, which class has special advantages.

We have discovered that by selection of particular substituents (namelya piperazin-1-yl substituent at the 4-position of the piperidine ring,substituted phenyl alkyl amide groups at the 1-position and substitutedphenyl groups at the 2-position) a class of compounds havingadvantageous properties in the treatment of conditions mediated bytachykinins is obtained.

DETAILED DESCRIPTION OF THE INVENTION

Thus the present invention provides compounds of formula (I)

wherein

-   R represents a halogen atom or a C₁₋₄ alkyl group;-   R₁ represents a C₁₋₄ alkyl group;-   R₂ represents hydrogen or a C₁₋₄ alkyl group;-   R₃ represents hydrogen, or a C₁₋₄ alkyl group;-   R₄ represents a trifluoromethyl group;-   R₅ represents hydrogen, a C₁₋₄ alkyl group or C(O)R₆;-   R₆ represents C1–4 alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄ alkyl) or    N(C₁₋₄alkyl)₂;-   m is zero or an integer from 1 to 3;-   n is an integer from 1 to 3;-   and pharmaceutically acceptable salts and solvates thereof.

A further embodiment of the invention provides compounds of formula (I)and pharmaceutically acceptable salts and solvates thereof, wherein

-   R represents a halogen atom or a C₁₋₄ alkyl group;-   R₁ represents a C₁₋₄ alkyl group;-   R₂ represents hydrogen or a C₁₋₄ alkyl group;-   R₃ represents hydrogen or a C₁₋₄ alkyl group;-   R₄ represents a trifluoromethyl group;-   R₅ represents hydrogen, a C₁₋₄ alkyl group or C(O)R₆;-   R₆ represents C₁₋₄ alkyl;-   m is zero or an integer from 1 to 3;-   n is an integer from 1 to 3.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids, for example hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

Suitable pharmaceutical acceptable salts of the compounds of generalformula (I) may be obtained in a crystalline form and/or in an amorphousform or as a mixture thereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least two chiral centres (namely the carbon atomsshown as * in formula (I)) and these may be represented by the formulae(1a, 1b, 1c and 1d).

The wedge shaped bond indicates that the bond is above the plane of thepaper and is referred to as β configuration. The broken bond indicatesthat the bond is below the plane of the paper and is in the aconfiguration.

In general, in the specific compounds named below the β configuration atthe 2 position corresponds to the R configuration and the βconfiguration at 4 position corresponds to the S configuration. The αconfiguration at the 2 position corresponds to the S configuration andthe α configuration at 4 position corresponds to the R configuration.The assignment of the R or S configuration at the 2 and the 4 positionshave been made according to the rules of Cahn, Ingold and Prelog ,Experientia 1956, 12, 81.

The configuration of the chiral carbons atom of the piperidine ringshown in 1a and 1b is hereinafter referred to as anti configuration andin formulae 1c and 1d as the syn configuration.

Further asymmetric carbon atoms are possible in the compound of formula(I). Thus, when R₂ and R₃ are not the same group, the compounds offormula (I) possess at least three asymmetric carbon atoms.

It is to be understood that all enantiomers and diastereoisomers andmixtures thereof are encompassed within the scope of the presentinvention.

The term alkyl as used herein as a group or a part of the group refersto a straight or branched alkyl group containing from 1 to 4 carbonatoms; examples of such groups include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl or tert butyl.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term C₃₋₇ cycloalkyl group means a non-aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A preferred group of compounds of formula (I) are those in which thecarbon atom at the 2-position of piperidine ring is in the βconfiguration. Within this group, those compounds in which the carbonatom at the 4-position is in the β configuration are particularlypreferred.

When R represents halogen this is suitably chlorine or more preferablyfluorine or when R is C₁₋₄ alkyl this is suitably methyl or ethylwherein m is zero or an integer from 1 to 2.

Suitable values for R₂ or R₃ include hydrogen, a methyl, an ethyl or apropyl group.

R is preferably a halogen (e.g. fluorine) and/or a C₁₋₄ alkyl (e.g.methyl) group and m is preferably zero or an integer from 1 to 2.

R₁ is preferably a methyl group.

R₂ is preferably a hydrogen atom or a methyl group.

R₃ is preferably a hydrogen atom or a methyl group.

R₅ is preferably a hydrogen atom, methyl, isopropyl or aC(O)cyclopropyl, a C(O)CH₃, a C(O)NHCH₃ or a C(O)N(CH₃)₂ group.

A preferred class of compounds of formula (I) are those wherein each Ris independently a halogen (e.g. fluorine) or a C₁₋₄ alkyl (e.g. methyl)group, wherein m is 0, 1 or 2. More preferably m is 1 or 2. Within thisclass those wherein R is at the 2 and/or 4 position in the phenyl ringare particularly preferred.

Compounds of formula (I), wherein n is 2, represent a preferred class ofcompounds and within this class the groups R₄ are preferably at the 3and 5 position in the phenyl ring.

A further preferred class of compounds of formula (I) is that wherein R₁is methyl, R₂ or R₃ represent independently hydrogen or a methyl group.

A particularly preferred group of compounds of formula (I) is thatwherein each R is independently halogen or methyl at the 2 and/or 4position, the groups R₄ are at the 3 and 5 position, R₁ is methyl, R₂and R₃ are independently hydrogen or methyl and R₅ is methyl, isopropylor a C(O)cyclopropyl, a C(O)CH₃, a C(O)NHCH₃ or a C(O)N(CH₃)₂ group, mis 1 or 2 and n is 2.

Preferred compounds according to the invention are:

-   4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(S)-[1-[(3,5Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic    acid, dimethylamide;-   4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylic    acid, methylamide;-   4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;-   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;    and pharmaceutically acceptable salts (e.g. hydrochloride,    methanesulphonate, sulphate, p-toluensulphonate) or solvates    thereof.

Further preferred compounds of the invention are:

-   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    methanesulphonate;-   4-(S)-(4-Acetyl-piperazin-1-y)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    sulfate;-   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride.

Particularly preferred compound of the invention is

-   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    methanesulphonate;

The compounds of the invention are antagonists of tachykinins, includingsubstance P and other neurokinins, both in vitro and in vivo and arethus of use in the treatment of conditions mediated by tachykinins,including substance P and other neurokinins.

NK₁-receptor binding affinity has been determined in vitro by thecompounds' ability to displace [3H]—substance P (SP) from recombinanthuman NK₁ receptors expressed in Chinese Hamster Ovary (CHO) cellmembranes.

CHO cell membranes were prepared by using a modification of the methoddescribed by Dam T and Quirion R (Peptides, 7:855–864, 1986). Thusligand binding was performed in 0.4 ml of 50 mM HEPES, pH 7.4,containing 3 mM MnCl₂, 0.02% BSA, 0.5 nM [³H]Substance P (30÷56 Ci/mmol,Amersham), a final membrane concentration of 25 μg of protein/ml, andthe test compounds. The incubation proceeded at room temperature for 40min. Non-specific binding was determined using excess of Substance P (1μM) and represents about 6% of the total binding. Compounds of theinvention were further characterised in a functional assay for thedetermination of their inhibitory effect. Human-NK₁-CHO cells werestimulated with Substance P and the receptor activation was evaluated bymeasuring the accumulation of cytidinediphosphodiacylglycerol (CDP-DAG),which is the liponucleotide precursor of phosphatidylinositoldiphosphate. CDP-DAG accumulates in the presence of Li⁺ as a consequenceof the receptor mediated activation of phospholipase C (PLC) (Godfrey,Biochem. J., 258:621–624, 1989). The method is described in detail byFerraguti et al. (Mol. Cell. Neurosci., 5:269–276, 1994).

The action of the compounds of the invention at the NK₁ receptor may bedetermined by using conventional tests. Thus the ability to penetratethe central nervous system and to bind at the NK₁ receptor wasdemonstrated in vivo by their inhibitory effect on the change in thebehaviour induced by intracerebroventricular applied substance P in thegerbil, according to the gerbil foot tapping model as described byRupniak & Williams, Eur. J. of Pharmacol., 1994.

Compounds of the invention are useful in the treatment of CNS disorders.In particular they are useful in the treatment or prevention of majordepressive disorders including bipolar depression, unipolar depression,single or recurrent major depressive episodes with or without psychoticfeatures, catatonic features, melancholic features, atypical features orpostpartum onset, the treatment of anxiety and the treatment of panicdisorders. Other mood disorders encompassed within the term majordepressive disorders include dysthymic disorder with early or late onsetand with or without atypical features, neurotic depression, posttraumatic stress disorders and social phobia; dementia of theAlzheimer's type, with early or late onset, with depressed mood;vascular dementia with depressed mood; mood disorders induced byalcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids,phencyclidine, sedatives, hypnotics, anxiolytics and other substances;schizoaffective disorder of the depressed type; and adjustment disorderwith depressed mood. Major depressive disorders may also result from ageneral medical condition including, but not limited to, myocardialinfarction, diabetes, miscarriage or abortion, etc.

Compounds of the invention have also been found to exhibit anxiolyticactivity in conventional tests. For example in marmoset human threattest (Costall et al., 1988).

Compounds of the invention are useful as analgesics. In particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of the cognitive disorders. Cognitive disorders includedementia, amnestic disorders and cognitive disorders not otherwisespecified.

Furthermore compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example,. they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds), or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of cocaine, sedative ipnotic,amphetamine or amphetamine-related drugs (e.g. dextroamphetamine,methylamphetamine) addiction or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome; skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

Compounds of the invention are of particular use in the treatment ofdepressive states, in the treatment of anxiety and of panic disorders.Depressive states include major depressive disorders including bipolardepression, unipolar depression, single or recurrent major depressiveepisodes with or without psychotic features, catatonic features,melancholic features, atypical features or postpartum onset, dysthymicdisorder with early or late onset and with or without atypical features,neurotic depression and social phobia; dementia of the Alzheimer's type,with early or late onset, with depressed mood; vascular dementia withdepressed mood; mood disorders induced by alcohol, amphetamines,cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives,hypnotics, anxiolytics and other substances; schizoaffective disorder ofthe depressed type.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants or dopaminergicantidepressants.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron, granisetronand metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbineand metoclopramide.

Suitable SSRI which may be used in combination with the compounds of theinvention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline and zimeldine.

Suitable SNRI which may be used in combination with the compounds of theinvention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations) or sequentially.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles.(e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅, R₆ m and n, have themeaning as previously defined for compounds of formula (I) unlessotherwise stated.

Compounds of formula (I) may be prepared by reductive N-alkylation of acompound of formula (II),

with a piperazine derivative (III) in an aprotic solvent such asdichloroethane and in the presence of a suitable metal reducing agentsuch as sodium borohydride or sodium triacetoxyborohydride.

Compounds of formula (II) may be prepared by treating compounds offormula (IV)

with triphosgene in an aprotic solvent such as dichloromethane and inthe presence of an organic base such triethylamine to form theintermediate carbonyl chloride compound (V) which may be isolated ifrequired, followedby reaction of compound (V) with the amine compound(VI)

The reaction conveniently takes place in an aprotic solvent such as ahydrocarbon, a halohydrocarbon such as dichloromethane or an ether suchas tetrahydrofuran optionally in the presence of a base such as atertiary amine e.g. diisopropylethylamine.

Where it is desired to isolate a compound formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compounds offormula (I) using conventional methods.

Compounds of formula (III), (IV), (V) and (VI) may be prepared byanalogous methods to those used for known compounds.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, for example, specific enantiomers of the compounds of formula (I)may be obtained from the corresponding enantiomeric mixture of acompound of formula (I) using chiral HPLC procedure.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Thus for example the required enantiomer may be prepared by thecorresponding a chiral piperidin-4-one of formula (IV) using the processdescribed above for preparing compounds of formula (I) from compounds(IV), followed by separation of the diastereomeric mixture of a compoundof formula(I) using conventional procedure.

The chiral compounds (IV) may be prepared from the corresponding racemiccompound (IV) using conventional procedures such as salt formation witha suitable optically active acid, separating the resultantdiastereoisomeric salts by conventional means e.g. chromatography andcrystallisation followed by hydrolysis of the diastereoisomeric salts. Asuitable optically active acid for use in the process is L(+)mandelicacid.

In a further embodiment of the invention the chiral compound (IV) may beprepared using Comins reaction as described in Journal American ChemicalSociety 1994, 116, 4719–4728, followed by reduction of 2,3dihydro-1H-pyridin-4-one derivative to piperidin-4-one derivative. Thereduction may be effected using hydrogen and metal catalyst e.g.palladium on a suitable support e.g. carbon or alumina. The reaction iscarried out in a solvent such as ester e.g. ethyl acetate.

In a further embodiment of the invention the enantiomers of the compoundof formula (I) may be prepared by reaction of a chiral amine (VI) usingany of the processes described above for preparing compounds of formula(I) from amine (V).

The chiral amine (III) may be prepared from the corresponding racemicamine (III) using any conventional procedures such as salt formationwith a suitable optically active acid.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention.

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Buchi m.p. apparatus and areuncorrected. R.T. or r.t. refer to room temperature.

Infrared spectra (IR) were measures in chloroform or nujol solutions ona FT-IR instrument. Proton Magnetic Resonance (NMR) spectra wererecorded on Varian instruments at 400 or 500 MHz, chemical shifts arereported in ppm (δ) using the residual solvent line as internalstandard. Splitting patterns are designed as s, singlet; d, double; t,triple; q, quartet; m, multiplet; b, broad. Mass spectra (MS) were takenon a VG Quattro mass spectrometer. Optical rotations were determined at20° C. with a Jasco DIP360 instrument (I=10 cm, cell volume=1 mL, λ=589nm). Flash silica gel chromatography was carried out over silica gel230–400 mesh supplied by Merck AG Darmstadt, Germany. T.l.c. refers tothin layer chromatography on 0.25 mm silica gel plates (60F-254 Merck)and visualized with UV light.

Solutions were dried over anhydrous sodium sulphate.

Methylene chloride was redistilled over calcium hydride andtetrahydrofuran was redistilled over sodium.

The following abbreviation are used in the text: AcOEt=ethyl acetate,CH=cyclohexane, DCM=methylene chloride, DIPEA=N,N-diisopropylethylamine,DMF=N,N′-dimethylformamide, Et2O=diethyl ether, EtOH=ethanol,MeOH=methanol, TEA=triethylamine, THF=tetrahydrofuran.

Intermediate 11-(Benzyloxycarbonyl)-2-(4-fluoro-2-methyl-phenyl)-2,3-dihydro-4-pyridone

A small amount of iodine was added to a suspension of magnesium turnings(13.2 g) in dry THF (300 mL), at r.t., under a nitrogen atmosphere, thenthe mixture was vigorously refluxed for 20 minutes. To this suspension,a 15% of a solution of 2-bromo-5-fluoro-toluene (52.5 mL) in anhydrousTHF (300 mL) was added. The suspension was heated under vigorous refluxuntil the brown colour disappeared. The remaining part of the bromidesolution was added drop-wise over 1 hour to the refluxing suspensionwhich was then stirred for a further 1 hour. This solution of Grignardreagent was then added dropwise to the pyridinium salt obtained frombenzyl chloroformate (48.7 mL) and 4-methoxypyridine (25 mL) in dry THF(900 mL) at −23° C.

The obtained solution was stirred 1 hour at −20° C. then it was warmedup to 20° C., a 10% hydrochloric acid solution (560 mL) was added andthe aqueous layer was extracted with AcOEt (2×750 mL).

The combined organic extracts were washed with 5% sodium hydrogencarbonate solution (600 mL) and brine (600 mL) then partiallyconcentrated in vacuo.

CH (400 mL) was added drop-wise over 1 hour at 20° C. and the resultingmixture was stirred 30 minutes and then filtered to give the titlecompound as a white solid (66 g).

IR (nujol, cm⁻¹): 1726 and 1655 (C═O), 1608 (C═C). NMR (d₆-DMSO): δ(ppm) 8.19 (d, 1H); 7.31–7.18 (m, 5H); 7.08 (m, 2H);6.94 (dt, 1H); 5.77(d, 1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H); 2.32 (d, 1H); 2.26(s, 3H). MS (ES/+): m/z=340 [MH]⁺.

Intermediate 2 2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one

Method A

2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) andthe solution was stirred at r.t. under a nitrogen atmosphere. After 1hour the mixture was heated at reflux for 16 hours and then allowed tocool to r.t. This solution was slowly added to a refluxing solution ofp-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previouslyrefluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours thecrude solution was cooled and made basic with a saturated potassiumcarbonate solution and taken up with AcOEt (50 mL). The aqueous phasewas extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layerwas dried and concentrated in vacuo to a yellow thick oil as residue(7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6Nhydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours.The solution was basified with solid potassium carbonate and extractedwith DCM (5×50 mL). The combined organic phases were washed with brine(50 mL), dried and concentrated in vacuo to give the title compound (2.5g) as a thick yellow oil.

Method B

L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL)previously cooled to −72° C. under a nitrogen atmosphere. After 45minutes, 2% sodium hydrogen carbonate solution (994 mL) was addeddrop-wise and the solution was extracted with AcOEt (3×994 mL). Thecombined organic phases were washed with water (284 mL) and brine (568mL). The organic phase was dried and concentrated in vacuo to get1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as apale yellow thick oil (94 g) which was used as a crude.

This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C(30.5 g) was added under a nitrogen atmosphere. The slurry washydrogenated at 1 atmosphere for 30 minutes. The mixture was filteredthrough Celite and the organic phase was concentrated in vacuo to givethe crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil.This material was dissolved in AcOEt (518 mL) at r.t. and racemiccamphorsulphonic acid (48.3 g) was added. The mixture was stirred atr.t. for 18 hours, then the solid was filtered off, washed with AcOEt(2×50 mL) and dried in vacuo for 18 hours to give2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acidsalt as a pale yellow solid (68.5 g). (M.p.: 167–169° C.-NMR (d₆-DMSO):δ (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97(bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37(s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03(s, 3H); 0.73 (s, 3H).

This material (68.5 g) was suspended in AcOEt (480 mL) and stirred witha saturated sodium hydrogen carbonate (274 mL). The organic layer wasseparated and washed with further water (274 mL). The organic phase wasdried and concentrated in vacuo to give the title compound (31 g) as ayellow-orange oil.

NMR (d₆-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27(m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29(s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).

MS (ES/+): m/z=208 [MH]⁺.

Intermediate 32-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid,(3,5-bis-trifluoromethyl-benzyl)-methylamide.

A solution of triphosgene (1.43 g) dissolved in dry DCM (10 mL) wasadded to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 mL) in dryDCM (20 mL) previously cooled to 0° C. under a nitrogen atmosphere. Thesolution was stirred at 0° C. for 2 hours, then(3,5-bis-trifluoromethyl-benzyl)-methylamine hydrochloride (5.63 g) andDIPEA (3.34 mL) were added. The mixture was stirred under nitrogen atr.t. for 14 hours. The mixture was taken up with AcOEt (50 mL), washedwith cold 1N hydrochloric acid solution (3×20 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/CH 3:7) to give the titlecompound as a white foam (3.85 g).

IR (nujol, cm⁻¹): 1721 and 1641 (C═O). NMR (d₆-DMSO): δ (ppm) 7.96 (s,1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H); 6.90 (dt, 1H); 5.22 (t,1H); 4.59 (d, 1H); 4.43 (d, 1H); 3.63–3.49 (m, 2H); 2.79 (s, 3H); 2.69(m, 2H); 2.49 (m, 2H); 2.26 (s, 3H). MS (ES/+): m/z=491 [MH]⁺.

Intermediate 42-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid,[1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-methylamide (4a) and2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid,[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (4b)

Method A

A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was addeddrop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) indry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere.After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylaminehydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL)were added and the mixture was heated to 70° C. for 16 hours. Further[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(170 mg) and DIPEA (100 μL) were added and the mixture was stirred at70° C. for further 4 hours. Next, the mixture was allowed to cool tor.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acidcold solution (3×15 mL) and brine (2×10 mL). The organic layer was driedand concentrated in vacuo to a residue, which was purified by flashchromatography (CH/AcOEt 8:2) to give:

-   1. intermediate 4a (230 mg) as a white foam,-   2. intermediate 4b (231 mg) as a white foam.

Intermediate 4a

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97(dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55(m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57(d, 3H).

Intermediate 4b

NMR (d₆-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98(dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48(m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).

Intermediate 4a

Method B

A saturated sodium hydrogen carbonate solution (324 mL) was added to asolution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resultingmixture was vigorously stirred for 15 minutes. The aqueous layer wasback-extracted with further AcOEt (216 mL) and the combined organicextracts were dried and concentrated in vacuo to give intermediate 8 asa yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). Thesolution obtained was added drop-wise over 40 minutes to a solution oftriphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under anitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.

After stirring for 1 hours at 0° C. and for 3 hours at 20° C.,[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reactionmixture which was then heated to reflux for 16 hours.

The solution was washed with 10% sodium hydroxide solution (180 mL), 1%hydrochloric acid solution (4×150 mL), water (3×180 mL) and brine (180mL). The organic layer was dried and concentrated in vacuo to a residue,which was purified through a silica pad (CH/AcOEt 9:1) to give the titlecompound (21.5 g) as a brown thick oil.

NMR (d₆-DMSO): δ (ppm) 7.97–7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd,1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m,2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 52-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid,[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (5a) and2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid,[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (5b)

A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was addedto a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM(15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2hours, a solution of[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(510 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) was added andthe mixture was heated to 70° C. for 16 hour. Next, further[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(170 mg) and DIPEA (105 μL) were added. After further 4 hours at 70° C.,the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL),washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine(2×10 mL). The organic layer was dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 8:2) togive:

-   1. intermediate 5a (234 mg) as a white foam,-   2. intermediate 5b (244 mg) as a white foam.

Intermediate 5a

NMR (d₆-DMSO): δ (ppm) 7.97–7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd,1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m,2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 5b

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97(dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55(m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57(d, 3H).

Intermediate 62-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylicacid, (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl Ester (6a) and2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylicacid, (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl Ester (6b)

A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 mL) wasdropped over 30 minutes, into a mixture of magnesium (525 mg) and iodine(1 crystal) in dry THF (5 mL) previously heated to 70° C. under anitrogen atmosphere. The mixture was stirred at 70° C. for 1.5 hours,then allowed to cool to r.t.

A solution of (−)-methyl chloroformate (3.53 mL) in dry THF (15 mL) wasadded to a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL)previously cooled to −78° C. under a nitrogen atmosphere. After 15minutes, the solution containing the 4-fluoro-2-methyl-phenyl magnesiumbromide was added drop-wise, and the mixture was stirred at −78° C. for1 hour. The reaction was quenched by the addition of 1M hydrochloricacid solution (20 mL), warmed to r.t. and stirred at 23° C. for 30minutes. After extraction with AcOEt (2×150 mL), the combined organicextracts were washed with brine (50 mL), dried and concentrated in vacuoto a residue, which was purified by flash chromatography (CH/THF/toluene8:1:1) to give:

-   1. intermediate 6a (3.44 g—yellow oil)-   2. intermediate 6b (530 mg—white solid).

Intermediate 6a

T.l.c.: CH/THF/toluene 7:2:1, Rf=0.59. IR (nujol, cm⁻¹): 1718 and 1675(C═O). NMR (d₆-DMSO): δ (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd,1H); 6.95 (m, 1H); 5.68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd,1H); 2.30 (m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m, 11H).

Intermediate 6b

M.p.: 117–120° C. T.l.c.: CH/THF/toluene 7:2:1, Rf=0.56. IR (nujol,cm⁻¹): 1718 and 1669 (C═O). NMR (d₆-DMSO): δ (ppm) 8.17 (d, 1H);7.04–6.94 (m, 3H); 5.70 (d, 1H); 5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd,1H); 2.30 (m, 4H); 1.58–1.40 (m, 3H); 1.2–0.7 (m, 8H); 0.51–0.34 (bs,6H).

Intermediate 72-(R)-(4-Fluoro-2-methyl-phenyl)-2,3-dihydro-1H-pyridin-4-one

Sodium methoxide (100 mg) was added to a solution of intermediate 6b(170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture wasrefluxed for two hours, and the solvent was removed in vacuo. Theresidue was partitioned between water (10 mL) and AcOEt (15 mL). Thelayers were separated, and the aqueous phase was extracted with furtherAcOEt (4×10 mL). The combined organic extracts were washed with brine(10 mL), dried and concentrated in vacuo to give the title compound (145mg) as a light yellow oil.

NMR (d₆-DMSO): δ (ppm) 7.71 (bd, 1H); 7.45 (dd, 1H); 7.38 (t, 1H); 7.03(m, 2H); 4.86 (dd, 1H); 4.77 (d, 1H); 2.42 (dd, 1H); 2.31 (m, 4H). MS(ES/+): m/z=206 [M+H]⁺.

Intermediate 8 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one

Palladium over charcoal (10%—74 mg) was added to a solution ofintermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). The mixture wasallowed to react with hydrogen in a pressure reactor (2 atm) overnight.After flushing with nitrogen, the solution was filtered and the solventremoved in vacuo. The crude product was purified by flash chromatography(AcOEt/MeOH 9:1) to give the title compound (26 mg) as a yellow oil.

The enantiomeric excess (90–95%) was detected by chiral HPLC.

T.l.c.: AcOEt/MeOH 9:1, Rf=0.2. NMR (d₆-DMSO): δ (ppm) 7.49 (dd, 1H);7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H);2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).MS (ES/+): m/z=208 [MH]⁺. [α]_(D)=+82.1 (c=1.07, DMSO).

Intermediate 9 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one MandelicAcid

A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was addedto a solution of intermediate 2 (31 g) in AcOEt (308 mL). Thenisopropanol (616 mL) was added and the solution was concentrated invacuo to 274 mL. The solution was then cooled to 0° C. and further coldisopropanol (96 mL) was added. The thick precipitate was stirred undernitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O(250 mL) to give the title compound as a pale yellow solid (20.3 g).

M.p.: 82–85° C. NMR (d₆-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32(m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31(m, 1H); 2.88 (m, 1H); 2.49–2.2 (m, 4H); 2.29 (s, 3H).

Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm×4.6 mm;mobile phase: n-hexane/isopropanol 95:5+1% diethylamine; flow: 1.3ml/min; detection: 240/215 nm; retention time 12.07 minutes.

Intermediate 102-(R)-4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid,(3,5-bis-trifluoromethyl-benzyl)-methylamide

Method A

A solution of triphosgene (17 mg) in dry DCM (2 mL) was added to asolution of intermediate 8 (26 mg) and DIPEA (65 mg) in dry DCM (3 mL)previously cooled to 0° C. under a nitrogen atmosphere. After two hoursacetonitrile (10 mL) was added, the temperature was allowed to reachr.t. and the DCM evaporated under a nitrogen flush. Then, a solution of3,5-(bis-trifluoromethyl-benzyl)-methylamine hydrochloride (74 mg) andDIPEA (130 mg) in acetonitrile (3 mL) was added and the mixture wasstirred at 23° C. overnight. The solvent was concentrated in vacuo. Theresidue was dissolved in AcOEt (10 mL) and washed with 1N hydrochloricacid solution (3×5 mL), 5% sodium hydrogen carbonate (5 mL) and brine(10 mL). The organic layer was dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 1:1) togive the title compound (50 mg) as a white solid.

Method B

A saturated sodium hydrogen carbonate solution (348 mL) was added to asolution of intermediate 9 (23.2 g) in AcOEt (348 mL) and the resultingmixture was vigorously stirred for 15 minutes. The aqueous layer wasback-extracted with further AcOEt (230 mL) and the combined organicextracts were dried and concentrated in vacuo to give intermediate 8(12.31 g) as a yellow oil, which was treated with TEA (20.5 mL) andAcOEt (123 mL). The solution obtained was added drop-wise over 40minutes to a solution of triphosgene (8 g) in AcOEt (61 mL) previouslycooled to 0° C. under a nitrogen atmosphere, maintaining the temperaturebetween 0° C. and 8° C. After stirring for 2 hours at 20° C.,3,5-(bis-trifluoromethyl-benzyl)-methylamine hydrochloride (28.1 g),AcOEt (184 mL) and TEA (33 mL) were added to the reaction mixture whichwas then further stirred for 2 hours at 20° C.

The solution was washed with 10% sodium hydroxide solution (3×185 mL)and 1% hydrochloric acid solution (3×185 mL). The organic layer wasdried and concentrated in vacuo to a crude (38 g), which was purifiedthrough a silica pad (CH/AcOEt from 9:1 to 1:1) to give the titlecompound (24.7 g) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98(dd, 1H); 6.90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60(m, 2H); 2.69 (m, 2H); 2.79 (s, 3H); 2.50 (m, 2H); 2.27 (s, 3H). MS(ES/+): m/z=491 [MH]⁺.

Intermediate 11 4-Cyclopropanoyl-piperazine-1-carboxylic acid,tert-butyl ester

Cyclopropanoyl chloride (112 μL) was added to a mixture ofN-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassiumcarbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. Themixture was stirred at r.t. for 18 hours, then it was filtered off frominorganics. The organic phase was diluted with Et2O (20 mL) and washedwith 1N hydrochloric acid solution (10 mL). The aqueous phase was madebasic with 1N sodium hydroxide solution and extracted twice with DCM.The combined organic layers were dried and concentrated in vacuo to givethe title compound (210 mg) as an oil.

T.l.c.: AcOEt, Rf=0.45.

NMR (d₆-DMSO): δ (ppm) 3.64–3.28 (m, 8H); 1.94 (m, 1H); 1.4 (s, 9H); 0.7(m, 4H).

MS (ES/+): m/z=255 [M+H]⁺.

Intermediate 12 1-Cyclopropanoyl-piperazine

TFA (965 μL) was added to a solution of intermediate 11 (210 mg) inanhydrous DCM (1 mL). The solution was stirred at r.t. for 2 hours, thenit was concentrated in vacuo. The residue was diluted in a saturatedpotassium carbonate solution (10 mL) and extracted with AcOEt (2×20 mL).The combined organic extracts were dried and concentrated in vacuo togive the title compound (110 mg) as an oil.

T.l.c.: AcOEt, Rf=0.14. IR (CDCl₃, cm⁻¹): 1626 (C═O). NMR (CDCl₃): δ(ppm) 3.7 (bs, 1H); 3.63 (bd, 4H); 2.88 (bd, 4H); 1.72 (m, 1H); 0.99 (m,2H); 0.75 (m, 2H). MS (ES/+): m/z=155 [M+H]⁺.

Intermediate 13 4-2-Methyl-propanoyl)-piperazine-1-carboxylic acid,tert-butyl ester

Isopropanoyl chloride (112 μL) was added to a mixture ofN-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassiumcarbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. Themixture was stirred at r.t. for 18 hours, then it was filtered off frominorganics. The organic phase was diluted with Et2O (20 mL) and washedwith 1N hydrochloric acid solution (10 mL). The aqueous phase was madebasic with 1N sodium hydroxide solution and extracted twice with DCM.The combined organic layers were dried and concentrated in vacuo and theresidue was purified by flash chromatography (AcOEt 100%) to give thetitle compound (133 mg) as a white solid.

T.l.c.: AcOEt, Rf=0.58. IR (nujol, cm⁻¹): 1703 and 1630 (C═O). NMR(d₆-DMSO): δ (ppm) 3.45–3.4 (m, 4H); 3.3–3.26 (m, 4H); 2.84 (m, 1H); 1.4(s, 9H); 0.97 (d, 6H). MS (ES/+): m/z=257 [M+H]⁺.

Intermediate 14 1-(2-Methyl-propanoyl)-piperazine

TFA (900 μL) was added to a solution of intermediate 13 (133 mg) inanhydrous DCM (10 mL). The solution was stirred at r.t. for 3.5 hours,then it was concentrated in vacuo. The residue was diluted in asaturated potassium carbonate solution (10 mL) and extracted with AcOEt(2×20 mL). The combined organic extracts were dried and concentrated invacuo to give the title compound (50 mg) as an oil.

T.l.c.: AcOEt, Rf=0.12. IR (CDCl₃, cm⁻¹): 1624 (C═O). NMR (CDCl₃): δ(ppm) 3.7 (bs, 2H); 3.5 (bs, 2H); 2.86 (m, 4H); 2.78 (m, 1H); 1.13 (d,6H). MS (ES/+): m/z=157 [M+H]⁺.

Intermediate 154-(R)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, tert-butyl ester (15a) and4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, tert-butyl ester (15b)

A solution of intermediate 10 (400 mg) andN-tert-butoxycarbonyl-piperazine (151.8 mg) in dry 1,2-dichloroethane(10 mL) was stirred at r.t. for 30 minutes under a nitrogen atmosphere.Then, sodium triacetoxyborohydride (310 mg) was added and the mixturewas stirred at 23° C. for 24 hours. The solution was diluted with AcOEtand washed with water. The organic layer was dried and concentrated invacuo to a residue, which was purified by flash chromatography(AcOEt/MeOH from 9:1) to give:

-   1. intermediate 15a (181 mg),-   2. intermediate 15b (155 mg).

Intermediate 15a:

T.l.c.: AcOEt/MeOH 8:2 Rf=0.35. IR (nujol, cm⁻¹): 1703 and 1651 (C═O).NMR (d₆-DMSO): δ (ppm) 7.91 (s, 1H); 7.65 (s, 2H); 7.26 (dd, 1H); 6.89(dd, 1H); 6.79 (bt, 1H); 4.78 (dd, 1H); 4.52 (d, 1H); 4.37 (d, 1H); 3.25(m, 6H); 3.09 (m, 1H); 2.78 (s, 3H); 2.37 (bs, 4H); 2.22 (s, 3H); 1.86(m, 1H); 1.78 (m, 1H); 1.68 (m, 2H); 1.35 (s, 9H). MS (ES/+): m/z=661[MH]⁺.

Intermediate 15b

T.l.c.: AcOEt/MeOH 8:2 Rf=0.14. IR (nujol, cm⁻¹): 1702 and 1654 (C═O).NMR (d₆-DMSO): δ (ppm) 7.90 (s, 1H); 7.56 (s, 2H); 7.18 (dd, 1H); 6.85(dd, 1H); 6.73 (dt, 1H); 4.59 (d, 1H); 4.32 (d, 1H); 4.1 (dd, 1H); 3.41(bm, 1H); 3.21 (bs, 4H); 2.87 (s, 3H); 2.64 (t, 1H); 2.5 (m, 1H); 2.39(bs, 4H); 2.3 (s, 3H); 1.82 (bs, 1H); 1.73 (m, 1H); 1.56 (dq, 1H); 1.33(s, 9H); 1.33 (q, 1H). MS (ES/+): m/z=661 [MH]⁺.

Intermediate 161-(Benzyloxycarbonyl)-2-(4-fluoro-phenyl)-2,3-dihydro-4-pyridone

A solution of benzyl chloroformate (48.7 mL) in dry THF (60 mL) wasadded to a solution of 4-methoxypyridine (25 mL) in dry THF (900 mL)previously cooled at −23° C. under a nitrogen atmosphere.

The mixture was stirred at −23° C. for 50 minutes, then p-fluorophenylmagnesium bromide (1M in THF—48.7 mL) was added. The solution wasstirred at −20° C. for 1 hour, then it was warmed up to 20° C. and a 10%hydrochloric acid solution (560 mL) was added. The aqueous layer wasextracted with AcOEt (1000 mL).

The organic extract was washed with 5% sodium hydrogen carbonatesolution (600 mL) and brine (600 mL) then partially concentrated invacuo. CH (200 mL) was added drop-wise over 1 hour at 20° C. and theresulting mixture was stirred at r.t. for 10 minutes, then at 0° C. for1.5 hours. The solid obtained was filtered off to give the titlecompound as a white solid (51.6 g).

NMR (d₆-DMSO): δ (ppm) 8.05 (d, 1H); 7.4–7.3 (m, 5H); 7.24 (dd, 2H);7.15 (t, 1H); 5.73 (d, 1H); 5.29 (d, 1H); 5.24 (dd, 2H); 3.25 (dd, 1H);2.62 (d, 1H); 2.26 (s, 3H). MS (EI/+): m/z=325 [M]⁺.

Intermediate 17 1-Benzyloxycarbonyl 2-(4-fluoro-phenyl)-piperidine-4-one

L-selectride (1M solution in THF, 62 mL) was added drop-wise, over 80minutes, to a solution of intermediate 16 (20 g) in dry THF (300 mL)previously cooled to −72° C. under a nitrogen atmosphere. After 45minutes, the solution was allowed to warm to −30° C. and 2% sodiumhydrogen carbonate solution (280 mL) was added drop-wise. The solutionwas extracted with AcOEt (3×280 mL). The combined organic phases werewashed with water (80 mL) and brine (160 mL). The organic phase wasdried and concentrated in vacuo to give the title compound as a paleyellow oil (27 g).

NMR (d₆-DMSO): δ (ppm) 7.26 (m, 7H); 7.17 (t, 2H); 5.53 (bt, 1H); 5.12(m, 2H); 4.1 (m, 1H); 3.44 (m, 1H); 3.01–2.84 (2dd, 2H); 2.54–2.3 (m,2H).

Intermediate 18 2-(4-Fluoro-phenyl)-piperidine-4-one

Intermediate 17 (94 g) was dissolved in AcOEt (300 mL), then 10% Pd/C(6.8 g) was added under a nitrogen atmosphere. The slurry washydrogenated at 1 atmosphere for 3 hours. The mixture was filteredthrough Celite and the organic phase was concentrated in vacuo to givethe crude 2-(4-fluoro-phenyl)-piperidine-4-one (10 g).

A part of this material (9 g) was purified by flash chromatography (fromCH/AcOEt 7:3 to AcOEt 100%) to give the title compound as a yellow oil(5 g).

NMR (d₆-DMSO): δ (ppm) 7.43 (m, 2H); 7.15 (m, 2H); 3.86 (dd, 1H); 3.29(m, 1H); 2.87 (bs, 1H); 2.81 (m, 1H); 2.48 (m, 1H); 2.42 (m, 1H); 2.33(m, 1H); 2.19 (m, 1H).

Intermediate 19 2-(4-Fluoro-phenyl)-piperidine-4-one, L-(+)-mandelate

L-(+)-mandelic acid (2.6 g) was added to a solution of intermediate 18(3.3 g) in acetone (50 mL) at r.t. The mixture was stirred at r.t. for 3hours and at 0° C. for 30 minutes, then the solid was filtered off togive the title compound as a white solid (4.4 g).

M.p.: 123–124° C. NMR (d₆-DMSO): δ (ppm) 7.39 (m, 2H); 7.35 (d, 2H);7.27 (t, 2H); 7.2 (t, 1H); 7.11 (t, 2H); 4.86 (s, 1H); 3.83 (dd, 1H);3.3–2.78 (m, 2H); 2.6–2.35 (m, 2H); 2.3–2.15 (m, 2H).

Intermediates 20a and 20b2-(R)-(4-Fluoro-phenyl)-4-oxo-piperidine-1-carboxylic acid,[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (20a) and2-(S)-(4-Fluoro-phenyl)-4-oxo-piperidine-1-carboxylic acid,[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (20b)

Intermediate 19 (600 mg) was treated with a saturated potassiumcarbonate solution (60 mL) and extracted with AcOEt (3×30 mL). Thecombined organic extracts were dried and concentrated in vacuo to give2-(4-fluoro-phenyl)-piperidine-4-one (267 mg). A solution of triphosgene(205 mg) dissolved in dry DCM (2 mL) was added drop-wise to a solutionof 2-(4-fluoro-phenyl)-piperidine-4-one (267 mg) and TEA (800 μL) in dryDCM (9 mL) previously cooled to 0° C. under a nitrogen atmosphere. Themixture was stirred at 0° C. for 3 hours and during this time furtherTEA (800 μL) andtriphosgene (205 mg) were added until completedisappearance of the starting material. Then,[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(560 mg) and DIPEA (1 mL) in dry acetonitrile (15 mL) were added and themixture was heated to 70° C. for 16 hours. The mixture was allowed tocool to r.t., taken up with AcOEt (30 mL), washed with a cold 1Nhydrochloric acid solution (3×15 mL) and brine (3×20 mL). The organiclayer was dried and concentrated in vacuo to a residue, which waspurified by flash chromatography (CH/AcOEt 7:3) to give:

-   3. intermediate 20a (140 mg) as a yellow oil,-   4. intermediate 20b (195 mg) as a yellow oil.

Intermediate 20a

T.l.c.: CH/AcOEt 1:1, Rf=0.65. IR (film, cm⁻¹): 1719 and 1636 (C═O). NMR(d₆-DMSO): δ (ppm) 8.0 (s, 1H); 7.87 (s, 2H); 7.3 (dd, 2H); 7.11 (t,2H); 5.19 (m, 2H); 3.68 (m, 1H); 3.36 (m, 1H); 2.8 (m, 2H); 2.66 (s,3H); 2.58 (m, 1H); 2.3 (m, 1H); 1.59 (d, 3H). MS (ES/+): m/z=491 [M+H]⁺.

Intermediate 20b

T.l.c.: CH/AcOEt 1:1, Rf=0.49. IR (film, cm⁻¹): 1721 and 1639 (C═O). NMR(d₆-DMSO): δ (ppm) 7.97 (s, 1H); 7.82 (s, 2H); 7.29 (dd, 2H); 7.1 (dd,1H); 5.21 (q, 1H) 5.11 (t, 1H); 3.6 (m, 1H); 3.46 (m, 1H); 2.85–2.7(2dd, 2H); 2.76 (s, 3H); 2.56 (m, 1H); 2.39 (m, 1H); 1.54 (d, 3H). MS(ES/+): m/z=491 [M+H]⁺.

EXAMPLE 14-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (1a)4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (1b)

A solution of intermediate 4a (120 mg), 1-acetylpiperazine (29.8 mg) andsodium triacetoxyborohydride (126 mg) in dry 1,2-dichloroethane (5 mL)was stirred at 23° C. for 24 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (15 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue which was purified by flash chromatography (AcOEt/MeOH 7:3)to give:

-   1.    4-(R)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    (40.0 mg—T.l.c.: AcOEt/MeOH 6:4 Rf=0.37),-   2.    4-(S)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    (30.0 mg—T.l.c.: AcOEt/MeOH 6:4 Rf=0.36).

EXAMPLE 24-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 1a (40.0 mg) in dry Et2O (5 mL) was treated withhydrochloric acid (1M in Et2O—1 mL). The resulting solution was stirredat 23° C. for 30 minutes, then it was concentrated in vacuo to give thetitle compound as a white solid (41.2 mg).

IR (nujol, cm⁻¹): 3416 (NH⁺), 1652 (C═O). NMR (d₆-DMSO): δ (ppm) 10.35(bs, 1H); 8.00 (s, 1H); 7.77 (s, 2H); 7.37 (dd, 1H); 7.01 (dd, 1H); 6.93(dt, 1H); 5.25 (bm, 1H); 5.06 (q, 1H); 4.44 (bm, 1H); 3.99 (m, 1H);3.70–3.45 (m, 4H); 3.20–2.90 (2m, 4H); 2.15 (m, 2H); 1.90–1.75 (2m, 3H);2.04 (s, 3H); 1.57 (d, 3H). MS (ES/+): m/z=617 [MH—HCl]⁺.

EXAMPLE 34-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 1b (30.0 mg) in dry Et2O (5 mL) was treated withhydrochloric acid (1M in Et2O—1 mL). The resulting mixture was stirredat 23° C. for 15 minutes, then filtered; the filtrate was treated withfurther dry Et2O (2 mL) to give the title compound as a whitish solid(26.5 mg).

IR (nujol, cm⁻¹): 3383 (NH⁺), 1650 (C═O). NMR (d₆-DMSO): δ (ppm) 11.17(bs, 1H); 7.98 (s, 1H); 7.67 (s, 2H); 7.21 (t, 1H); 6.94 (dd, 1H); 6.82(dt, 1H); 5.3 (q, 1H); 4.4 (bd, 1H); 4.18 (dd, 1H); 3.96–3.42 (m, 5H);3.10–2.70 (m, 4H); 2.72 (s, 3H); 2.43 (s, 3H); 2.17 (m, 2H); 2.00 (s,3H); 1.73–1.24 (m, 3H); 1.45 (d, 3H).

MS (ES/+): m/z=617 [MH—HCl]⁺.

EXAMPLE 44-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidemethanesulphonate

A solution of intermediate 4a (7.7 g) in acetonitrile (177 mL) was addedto a solution of 1-acetyl-piperazine (3.9 g) in acetonitrile (17.7 mL)followed by sodium triacetoxyborohydride (6.4 g) under a nitrogenatmosphere.

The reaction mixture was stirred at room temperature for 24 hours andthen quenched with a saturated sodium hydrogen carbonate (23.1 mL) andwater (61.6 mL). The resulting solution was concentrated in vacuo, thenAcOEt (208 mL) was added; the layers were separated and the aqueouslayer was back-extracted with further AcOEt (2×77 mL). The collectedorganic phases were washed with brine (2×118 mL), dried and concentratedin vacuo to give the crude mixture of syn and anti diastereomers (nearly1:1) as a white foam (9.5 g).

A solution of this intermediate in THF (85.4 mL) was added to a solutionof methansulfonic acid (0.890 mL) in THF (6.1 mL) at r.t. After seeding,the desired syn diastereomer started to precipitate. The resultingsuspension was stirred for 3 hours at 0° C. and then filtered under anitrogen atmosphere. The resulting cake was washed with cold THF (15.4mL) and dried in vacuo at +20° C. for 48 hours to give the titlecompound as a white solid (4.44 g).

NMR (d₆-DMSO): δ (ppm) 9.52 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 2H); 7.23(m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (bd, 1H); 4.20(dd, 1H); 3.99 (bd, 1H); 3.65–3.25 (bm, 5H); 3.17 (m, 1H); 2.96 (m, 1H);2.88–2.79 (m+m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13–2.09(bd+bd, 2H); 2.01 (s, 3H); 1.89–1.73 (m+m, 2H); 1.46 (d, 3H). m.p 243.0°C.

The compound is isolated in a crystalline form.

EXAMPLE 54-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide sulfate

Sulfuric acid 96% was added (0.06 mL) to a solution of example 1b (0.65g) in THF (6.5 mL) at 23° C. under a nitrogen atmosphere. The suspensionwas stirred at 23° C. for 15 hours, then cooled to 4° C., stirred for 4hours and allowed to warm to r.t. The solid was filtered off and driedat 23° C. for 18 hours to give the title compound (0.681 g).

NMR (d₆-DMSO): δ (ppm) 9.58 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 2H); 7.23(m, 1H); 6.95 (dd, 1H); 6.83 (m, 1H); 5.31 (q, 1H); 4.45 (bd, 1H); 4.20(d, 1H); 3.98 (bm, 1H); 3.65–3.30 (bm, 5H); 3.20–2.70 (bm, 4H); 2.74 (s,3H); 2.36 (s, 3H); 2.13 (bd, 1H); 2.08 (bd, 1H); 2.02 (s, 3H); 1.87 (m,1H); 1.72 (m, 1H); 1.46 (d, 3H). m.p. 237.4

The compound is isolated in a crystalline form.

EXAMPLE 64-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amidep-toluenesulfonate

Para-toluenesulfonic acid monohydrate (0.20 g) was added to a solutionof example 1b (0.65 g) in THF (6.5 mL) at 23° C. under a nitrogenatmosphere. Isooctane (10 mL) was added and the suspension was stirredat 23° C. for 24 hours. The solid was filtered off and dried at 23° C.for 18 hours to give the title compound (0.567 g).

NMR (d₆-DMSO): δ (ppm) 9.53 (bs, 1H); 8.00 (bs, 1H); 7.68 (bs, 2H); 7.46(d, 2H); 7.22 (bm, 1H); 7.10 (d, 2H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.30(q, 1H); 4.45 (bd, 1H); 4.19 (d, 1H); 3.99 (bm, 5H); 3.65–3.05 (m, 3H);3.05–2.70 (m, 2H); 2.73 (s, 3H); 2.35 (s, 3H); 2.27 (s, 3H); 2.12 (m,1H); 2.07 (m, 1H); 2.02 (s, 3H) 1.87 (m, 1H); 1.72 (m, 1H); 1.46 (d,3H).

EXAMPLES 74-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (7a)4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (7b)

A solution of intermediate 10 (86.7 mg), 1-acetylpiperazine (22 mg) andsodium triacetoxyborohydride (67 mg) in dry 1,2-dichloroethane (5 mL)was stirred at 23° C. for 24 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (15 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue which was purified by flash chromatography (AcOEt/MeOH 7:3)to give:

-   1.    4-(R)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide (34.6 mg    hereinafter compound 1);-   2.    4-(S)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide (19 mg    hereinafter compound 2).

EXAMPLE 7a

A solution of compound 1 (33 mg) in dry Et2O (2 mL) was treated withhydrochloric acid (1M in Et2O—0.5 mL). The resulting solution wasstirred at 23° C. for 30 minutes. The solution was concentrated in vacuoto give the title compound as a white foam (30 mg).

IR (nujol, cm⁻¹): 3395 (NH⁺), 1632 (C═O). NMR (d₆-DMSO): δ (ppm) 10.35(bs, 1H); 7.98 (bs, 1H); 7.8 (bs, 2H); 7.37 (dd, 1H); 7.0 (dd, 1H); 6.92(m, 1H); 5.24 (m, 1H); 4.57 (d, 1H); 4.41 (d, 1H); 4.45 (bm, 1H); 3.99(bm, 1H); 3.8–3.4 (bm, 6H); 3.2–2.8 (m, 4H); 2.73 (s, 3H); 2.34 (2H);2.23 (s, 3H); 2.03 (s, 3H); 2.17 (1 H); 1.69 (m, 1H). MS (ES/+): m/z=603[MH—HCl]⁺.

EXAMPLE 7b

A solution of compound 2 (19 mg) in dry Et2O (5 mL) was treated withhydrochloric acid (1M in Et2O—1 mL). The resulting mixture was stirredat 23° C. for 15 minutes, then concentrated in vacuo to give the titlecompound as a white foam (14 mg).

IR (nujol, cm⁻¹): 3387 (NH⁺), 1652 (C═O). NMR (d₆-DMSO): δ (ppm) 11.77(bs, 1H); 7.94 (s, 1H); 7.58 (s, 2H); 7.24 (t, 1H); 6.93 (dd, 1H); 6.81(m, 1H); 4.62 (d, 1H); 4.4 (dd, 1H); 4.35 (d, 1H); 4.19 (dd, 1H);3.8–3.4 (m, 4H); 3.2–2.7 (m, 4H); 3.9–1.25 (m, 6H); 2.92 (s, 3H); 2.35(s, 3H); 2.00 (s, 3H).

MS (ESI+): m/z=603 [MH—HCl⁺, 625 [M−HCl+Na]⁺.

EXAMPLE 82-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of intermediate 4a (100 mg), N-methylpiperazine (22 μL) andsodium triacetoxyborohydride (64 mg) in dry 1,2-dichloroethane (5 mL)was stirred at 23° C. for 6 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (10 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue, which was purified by flash chromatography (AcOEt/MeOHfrom 95:5 to 8:2) to give2-(R)-(4-fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-1-piperazinyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (57 mgT.l.c.: AcOEt/MeOH 8:2, Rf=0.2) which was dissolved in in dry Et2O (5mL) and then treated with hydrochloric acid (1M in Et2O—2 mL) and theresulting solution was stirred at 23° C. for 5 minutes. The solution wasconcentrated in vacuo to give a solid which was triturated in Et2O (2mL) to give the title compound as a white solid (35.4 mg).

IR (nujol, cm⁻¹): 3405 (NH₂ ⁺), 1639 (C═O). NMR (d₆-DMSO): δ (ppm) 7.95(s, 2H); 7.71 (s, 2H); 7.67 (s, 2H); 7.26 (dd, 1H); 7.15 (dd, 1H); 6.93(dd, 1H); 6.87 (dd, 1H); 6.82 (m, 1H); 6.74 (m, 1H); 5.32 (q, 1H); 5.16(q, 1H); 4.84 (m, 1H); 4.12 (dd, 1H); 3.5–3.0 (m, 3H); 2.69 (s, 3H);2.61 (s, 3H); 2.32 (s, 3H); 2.24 (s, 3H); 2.13 (s, 3H); 2.09 (s, 3H);2.5–1.5 (m, 12H); 1.50 (d, 3H); 1.45 (d, 3H). MS (ES/+): m/z=589[MH—HCl]⁺.

EXAMPLE 92-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of intermediate 4a (160 mg), N-tert-butoxycarbonyl-piperazine(60 mg) and sodium triacetoxyborohydride (100 mg) in dry1,2-dichloroethane (12 mL) was stirred at 23° C. for 24 hours under anitrogen atmosphere. The solution was washed with a 5% sodium hydrogencarbonate solution (20 mL) and brine (20 mL). The organic layer wasdried and concentrated in vacuo to a residue, which was purified byflash chromatography (CH/AcOEt from 1:1 to 3:7) to give:

-   1.    2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-[(4-tert-butoxycarbonyl)-piperazin-1-yl]-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (74    mg—T.l.c.: CH/AcOEt 1:1, Rf=0.35 hereinafter compound 1)-   2.    -2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-[(4-tert-butoxycarbonyl)-piperazin-1-yl]-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (48    mg—T.l.c.: CH/AcOEt 1:1, Rf=0.19 hereinafter compound 2)

Trifluoroacetic acid (1 mL) was added drop-wise at 0° C. to a solutionof compound 2 (48 mg) in dry DCM (3 mL). The solution was stirred for 1hour at the same temperature and for 1 hour at r.t. Then the solvent wasremoved in vacuo and the crude dissolved in AcOEt (5 mL). The resultingsolution was washed with a saturated potassium carbonate solution anddried. After concentration in vacuo, the crude2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (18 mg)was dissolved in dry Et2O (1 mL) and was then treated with hydrochloricacid (1M in Et2O—220 μL) at 0° C. The resulting mixture was stirred atr.t. for 30 minutes, then filtered and triturated with n-pentane to givethe title compound as a whitish solid (15 mg).

IR (nujol, cm⁻¹): 1653 (C═O). NMR (d₆-DMSO): δ (ppm) 7.94 (s, 1H); 7.59(s, 2H); 7.22 (dd, 1H); 6.89 (dd, 1H); 6.77(m, 1H); 4.62 (d, 1H); 4.36(d, 1H); 4.13 (dd, 1H); 3.44 (m, 1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m,1H); 2.65 (m, 4H); 2.4 (bm, 4H); 2.34 (s, 3H); 1.86 (bd, 1H); 1.77 (bd,1H); 1.6 (dq, 1H); 1.34 (q, 1H). MS (ES/+): m/z=561 [MH—HCl]⁺.

EXAMPLE 102-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide dihydrochloride

A solution of intermediate 10 (120 mg) and N-methylpiperazine (41 μL) indry 1,2-dichloroethane (2 mL) and acetonitrile (2 mL) was stirred atr.t. for 1 hour under a nitrogen atmosphere. Then sodiumtriacetoxyborohydride (78 mg) was added and the mixture was stirred at23° C. for 18 hours. The solution was washed with a 5% sodium hydrogencarbonate solution (10 mL) and extracted with DCM (2×10 mL). Thecombined organic extracts were washed with brine (10 mL), dried andconcentrated in vacuo to a residue, which was purified by flashchromatography (AcOEt/MeOH 1:1) to give2-(R)-(4-fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl)-benzyl-methylamide (115 mg T.l.c.:AcOEt/MeOH 1:1, Rf=0.09), which was dissolved in dry Et2O (5 mL) thentreated with hydrochloric acid (1M in Et2O—0.5 mL) and the resultingmixture was stirred at 23° C. for 5 minutes. The mixture wasconcentrated in vacuo to a solid which was triturated in Et2O (2 mL) togive the title compound as a whitish solid (115 mg).

M.p.: 208–9° C. IR (nujol, cm⁻¹): 3384 (NH⁺), 1645 (C═O). NMR (d₆-DMSO):δ (ppm) 7.9 (s, 1H); 7.7 (s, 1H); 7.59 (s, 1H); 7.4 (s, 1H); 7.24 (t,1H); 6.95–6.82 (m, 2H); 4.63 (d, 1H); 4.59 (d, 1H); 4.36 (d, 1H); 4.21(d, 1H); 4.19 (d, 1H); 2.93 (s, 3H); 2.37 (s, 3H); 2.27 (s, 3H); 3.7–1.0(m, 17H). MS (ES/+): m/z=575 [M+H−2HCl]⁺.

EXAMPLE 114-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (11 a)4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (11b)

A solution of intermediate 4a (100 mg) and intermediate 12 (31 mg) indry 1,2-dichloroethane (5 mL) and acetonitrile (1 mL) was stirred atr.t. for 30 minutes under a nitrogen atmosphere. Then, sodiumtriacetoxyborohydride (42 mg) was added and the mixture was stirred at23° C. for 24 hours. The solution was diluted with AcOEt and washed withwater. The organic layer was dried and concentrated in vacuo to aresidue which was purified by flash chromatography (AcOEt/MeOH 9:1) togive:

-   example 11a (2 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.33),-   example 11b (7 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.16).

EXAMPLE 124-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 11b (7 mg) in dry Et2O (5 mL) was treated withhydrochloric acid (1M in Et2O—40μL). The resulting mixture was stirredat 23° C. for 15 minutes, then concentrated in vacuo to give the titlecompound as a whitish solid (7.2 mg).

IR (nujol, cm⁻¹): 3.395 (NH⁺), 1644 (C═O). NMR (d₆-DMSO): δ (ppm) 10.13(bs, 1H); 8.0 (bs, 1H); 7.69 (s, 2H); 7.23 (m, 1H); 6.96 (m, 1H); 6.84(m, 1H); 5.31 (bq, 1H); 4.44 (bm, 2H); 4.2 (bd, 1H); 3.7–2.9 (bm, 5H);2.8 (t, 4H); 2.75 (s, 3H); 2.37 (s, 3H); 2.16 (m, 2H); 1.99 (m, 1H);2.0–1.5 (m, 2H); 1.47 (d, 3H); 0.87 (m, 2H); 0.74 (m, 2H). MS (ES/+):m/z=643 [MH—HCl]⁺.

EXAMPLE 134-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (13a)4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(13b)

A solution of intermediate 4a (100 mg) and intermediate 14 (30 mg) indry 1,2-dichloroethane (5 mL) was stirred at r.t. for 30 minutes under anitrogen atmosphere. Then, sodium triacetoxyborohydride (42 mg) wasadded and the mixture was stirred at 23° C. for 24 hours. The solutionwas diluted with AcOEt and washed with water. The organic layer wasdried and concentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/MeOH from 9:1 to 8:2) to give:

-   example 13a (15 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.33),-   example 13b (27.5 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.25).

EXAMPLE 144-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 13b (27.5 mg) in dry Et2O (1 mL) was treated withhydrochloric acid (1M in Et2O—60 μL). The resulting mixture was stirredat 23° C. for 15 minutes, then concentrated in vacuo. The residue wastriturated with pentane to give the title compound as a whitish solid(25.8 mg).

IR (nujol, cm⁻¹): 3395 (NH⁺), 1641 (C═O). NMR (d₆-DMSO): δ (ppm) 10.37(bs, 1H); 8.0 (s, 1H); 7.68 (s, 2H); 7.22 (dd, 1H); 6.94 (dd, 1H); 6.83(bt, 1H); 5.31 (bq, 1H); 4.46 (bm, 1H); 4.18 (bd, 1H); 4.12 (m, 1H);3.6–3.4 (m, 5H); 3.1–2.7 (m, 5H); 2.73 (s, 3H); 2.36 (s, 3H); 2.18–2.11(m, 2H); 1.89 (bq, 1H); 1.73 (q, 1H); 1.46 (d, 3H); 0.98 (bs, 6H).

EXAMPLE 154-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide hydrochloride

TEA (74.6 μL) and triphosgene (13.2 mg) were added to a solution ofexample 17 (50 mg) in anhydrous DCM (2 mL) under a nitrogen atmosphere.The solution was stirred at 23° C. for 2 hours, then DIPEA (31.9 μL) anddimethylamine (2M solution in THF—49 μL) were added. The mixture wasstirred at 23° C. for 18 hours, then poured into 1M hydrochloric acidsolution (10 mL) and extracted with AcOEt (2×20 mL). The combinedorganic extracts were dried and concentrated in vacuo to give4-(S)-[1-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide (60 mg). A solution of this compound (60 mg) in dryEt2O (1 mL) was treated with hydrochloric acid (1M in Et2O—100 μL). Theresulting mixture was stirred at 23° C. for 15 minutes, thenconcentrated in vacuo. The residue was triturated with petroleum to givethe title compound as a whitish solid (52 mg).

IR (nujol, cm⁻¹): 3382 (NH⁺), 1652 (C═O). NMR (d₆-DMSO): δ (ppm) 10.34(bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.26 (m, 1H); 6.94 (dd, 1H); 6.84(m, 1H); 4.63 (d, 1H); 4.36 (d, 1H); 4.2 (dd, 1H); 3.6–3.4 (m, 5H);3.4–3.1 (m, 5H); 2.93 (s, 3H); 2.75 (s, 6H); 2.7 (m, 1H); 2.36 (s, 3H);2.17 (m, 2H); 1.9–1.65 (m, 2H). MS (ES/+): m/z=632 [MH—HCl]⁺.

EXAMPLE 164-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide hydrochloride

TEA (74.6 μL) and triphosgene (13.2 mg) were added to a solution ofexample 17 (50 mg) in anhydrous DCM (2 mL) under a nitrogen atmosphere.The solution was stirred at 23° C. for 2 hours, then DIPEA (31.9 μL) andmethylamine (2M solution in THF—49 μL) were added. The mixture wasstirred at 23° C. for 18 hour, then poured into 1M hydrochloric acidsolution (10 mL) and extracted with AcOEt (2×20 mL). The combinedorganic extracts were dried and concentrated in vacuo to give4-(S)-[1-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide (65.3 mg).

A solution of this compound (60 mg) in dry Et2O (1 mL) was treated withhydrochloric acid (1M in Et2O—100 μL). The resulting mixture was stirredat 23° C. for 15 minutes, then concentrated in vacuo. The residue wastriturated with petroleum to give the title compound as a whitish solid(55 mg).

IR (nujol, cm⁻¹): 3351 (NH⁺), 1652 (C═O). NMR (d₆-DMSO): δ (ppm) 10.35(bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.25 (m, 1H); 6.94 (dd, 1H); 6.84(m, 1H); 6.68 (bs, 1H); 4.63 (d, 1H); 4.36 (d, 1H); 4.18 (dd, 1H); 4.0(m, 1H); 3.6–3.4 (m, 5H); 3.1–2.9 (m, 4H); 2.93 (s, 3H); 2.73 (m, 1H);2.56 (s, 3H); 2.36 (s, 3H); 2.19 (m, 2H); 1.9 (m, 1H); 1.7 (m, 1H). MS(ES/+): m/z=618 [MH—HCl]⁺.

EXAMPLE 174-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine

TFA (1 mL) was added to a solution of intermediate 15b (155 mg) inanhydrous DCM (5 mL). The solution was stirred at r.t. for 3 hours, thenit was concentrated in vacuo. The residue was diluted in a saturatedpotassium carbonate solution (10 mL) and extracted with DCM (2×20 mL)and AcOEt (20 mL). The combined organic extracts were dried andconcentrated in vacuo to give the title compound (104 mg) as an oil.

T.l.c.: AcOEt/MeOH 8:2 Rf=0.12. IR (nujol, cm⁻¹): 1653 (C═O). NMR(d₆-DMSO): δ (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.22 (dd, 1H); 6.89 (dd,1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.44 (dt,1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m, 1H); 2.65 (m, 4H); 2.4 (bm, 4H);2.34 (s, 3H); 1.86 (bd, 1H); 1.77 (bd, 1H); 1.6(dq, 1H); 1.34 (q, 1H).MS (ES/+): m/z=561 [MH]⁺.

EXAMPLE 184-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(18a)4-(S)-(4-acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(18b)

A solution of intermediate 20a (140 mg), 1-acetylpiperazine (73 mg) andsodium triacetoxyborohydride (121 mg) in dry acetonitrile (8 mL) wasstirred at 23° C. for 24 hours under a nitrogen atmosphere. Then,further sodium triacetoxyborohydride (60 mg) was added and the solutionwas stirred for a further 1 hour. The solution was diluted with AcOEt(20 mL) and washed with a saturated sodium hydrogen carbonate solution(15 mL) and brine (10 mL). The organic layer was dried and concentratedin vacuo to a residue, which was purified by flash chromatography(AcOEt/MeOH from 9:1 to 8:2) to give:

-   compound 18a (4 mg) T.l.c.: AcOEt/MeOH 8:2 Rf=0.48);-   compound 18b (20 mg) T.l.c.: AcOEt/MeOH 8:2 Rf=0.40).

EXAMPLE 194-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of 18b (20 mg) in dry Et2O (1 mL) was treated at −8° C. withhydrochloric acid (1M in Et2O—0.5 mL). The resulting mixture was stirredat 0° C. for 10 minutes, then filtered; the filtrate was triturated withdry pentane (2×2 mL) to give the title compound as a whitish solid (14.7mg).

NMR (d₆-DMSO): δ (ppm) 10.15 (bs, 1H); 7.91 (s, 1H); 7.68 (s, 2H); 7.26(m, 2H); 7.01 (m, 2H); 5.28 (q, 1H); 4.4 (bd, 1H); 4.09 (dd, 1H);3.8–3.4 (m, 5H); 3.8–2.8 (m, 4H); 3.1–2.7 (m, 4H); 2.01 (s, 3H); 2.2–1.8(m, 4H); 1.47 (d, 3H). MS (ES/+): m/z=603 [MH—HCl]⁺.

Pharmacy Examples

A. Capsules/Tablets Active ingredient 20.0 mg Starch 1500 2.5 mgMicrocrystalline 200.0 mg Cellulose Croscarmellose Sodium 6.0 mgMagnesium Stearate 1.5 mg

The active ingredient is blended with the other excipients. The blendcan be used to fill gelatin capsules or compressed to form tablets usingappropriate punches. The tablets can be coated using conventionaltechniques and coatings.

B. Tablets Active ingredient 20.0 mg Lactose 200.0 mg Microcrystalline70.0 mg Cellulose Povidone 25.0 mg Croscarmellose Sodium 6.0 mgMagnesium Stearate 1.5 mg

The active ingredient is blended with lactose, microcrystallinecellulose and part of the croscarmellose sodium. The blend is granulatedwith povidone after dispersing in a suitable solvent (i.e. water). Thegranule, after drying and comminution is blended with the remainingexcipients. The blend can be compressed using appropriate punches andthe tablets coated using conventional techniques and coatings.

c) Bolus Active ingredient 2–60 mg/ml Sodium phosphate 1.0–50.0 mg/mlwater for injection qs to 1 ml

The formulation may be packed in glass ampoules or vials and syringeswith a rubber stopper and a plastic/metal overseal (vials only).

D) Infusion Active ingredient 2–60 mg/ml Infusion solution (NaCl 0.9% or5% dextrose) qs to 100 ml

The formulation may be packed in glass vials or plastic bag.

The affinity of the compound of the invention for NK1 receptor wasdetermined using the NK₁-receptor binding affinity method measuring invitro by the compounds' ability to displace [3H]—substance P (SP) fromrecombinant human NK₁ receptors expressed in Chinese Hamster Ovary (CHO)cell membranes. The affinity values are expressed as negative logarithmof the inhibition constant (Ki) of displacer ligands (pKi).

The pKi values obtained as the average of at least two determinationswith representative compounds of the invention are given in thefollowing table:

Example No pki  2 9.36  3 10.29  7a 9.15  7b 10.13  8 9.68  9 9.93 109.94 12 9.91 14 10.00 15 10.34 16 10.36 19 9.38

The ability of the compounds of the invention to penetrate the centralnervous system and to bind at the nk1 receptor may be determined usingthe gerbill foot tapping model as described by Rupniak & Williams, Eur.Jour. of Pharmacol., 1994.

The compound was orally administered and four hours later an NK1 agonist(e.g. delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11)) (3 pmol in5 μL icv) was infused directly in the cerebral ventricules of theanimals. The duration of hind foot tapping induced by the NK1 agonist(e.g. delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11)) wasrecorded continuosly for 3 min using a stopclock. The dose of the testcompound required to inhibit by 50% the tapping induced by the NK1agonist (e.g. delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11))expressed as mg/kg is referred as the ED₅₀ values. Alternatively thecompounds may be administered subcutaneously or intraperitoneally.

Representative results obtained for compounds of the invention whengiven by oral administration are given in the following table

Ex N° ED_(50 (mg/kg))  3 0.05  7b 0.19 12 0.27

Examples Nos. 47, 49 and 52 described in WO 97/16440 have shown in thegerbil foot tapping model no ability up to 1 mg/Kg to penetrate thecentral nervous system when orally administered 4 hours before theadministration of an NK1 agonist (e.g.delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11)) (3 pmol in 5 μLicv).

No untoward effects have been observed when compounds of the inventionhave been administered to the gerbil at the pharmacological activedoses.

1. A compound of formula (I)

wherein each R independently represents a halogen atom or a C₁₋₄ alkylgroup; R₁ represents a C₁₋₄ alkyl group; R₂ represents hydrogen or aC₁₋₄ alkyl group; R₃ represents hydrogen or C₁₋₄ alkyl group; R₄represents a trifluoromethyl group; R₅ represents hydrogen, a C₁₋₄ alkylgroup or C(O)R₆; R₆ represents C₁₋₄ alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄alkyl) or N(C₁₋₄alkyl)₂; m is zero or an integer from 1 to 3; n is aninteger from 1 to 3; or a pharmaceuticaly acceptable salt or solvatethereof.
 2. A compound as claimed in claim 1 wherein the carbon atom atthe 2-position in the piperidine ring is in the β configuration.
 3. Acompound as claimed in claim 1 wherein m is 1 or 2, each R isindependently a halogen atom or a C₁₋₄ alkyl group at the 2 and/or4-positions in the phenyl ring.
 4. A compound as claimed in claim 1wherein n is 2 and the groups R₄ are at the 3 and 5-positions in thephenyl ring.
 5. A compound as claimed in claim 1 wherein m is 1 or 2,each R is independently halogen or methyl at the 2 and/or 4 position inthe phenyl ring, n is 2, the R₄ groups are at the 3 and 5-positions, R₁is methyl, R₂ and R₃ are independently hydrogen or methyl and R₅ ismethyl, isopropyl, a C(O)cyclopropyl, a C(O)CH₃, a C(O)NH₃ or aC(O)N(CH₃)₂ group.
 6. A compound selected from4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methytamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-Phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide:2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-pheny)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(S)-(4-Cyclopropanoyt-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bls-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-pheriyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[1-[(3,5-Bis-trifluoromettyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof.
 7. Apharmaceutical composition comprising a compound as claimed in claim 1.8. A method for the treatment of a condition mediated by a tachykinin,in a mammal in need thereof, comprising administering an effectiveamount of a compound as claimed in claim
 1. 9. A process for thepreparation of a compound as claimed in claim 1, which comprisesreacting a compound of formula (II),

with a piperazine (III) in the presence of a suitable metal reducingagent wherein R, R₁, R₂, R₃, R₄, R₅, m and n are as defined in claim 1.10. The pharmaceutical composition according to claim 7 furthercomprising one or more pharmaceutically acceptable carriers orexcipiants.
 11. The method according to claim 8, wherein said mammal isman.
 12. The method according to claim 8, wherein said tachykinin is aneurokinin.
 13. The method according to claim 8, wherein said tachykininis substance P.
 14. A method for the treatment of a CNS disorder in amammal comprising administering an effective amount of a compound asclaimed in claim
 1. 15. The method according to claim 14, wherein saidCNS disorder is selected from the group consisting of major depressivedisorders; single or recurrent major depressive episodes with or withoutpsychotic features, catatonic features, melancholic features, atypicalfeatures or postpartum onset; anxiety; and panic disorders.
 16. Themethod according to claim 15, wherein said major depressive disorder isselected from the group consisting of dysthymic disorder with early orlate onset and with or without atypical features; neurotic depression;post traumatic stress disorders; social phobia; dementia of theAizheimer's type, with early or late onset, with depressed mood;vascular dementia with depressed mood; mood disorders induced byalcohol, amphetamines, cocaine, hallucinogens, inhalants, oploids,phencyclidine, sedatives, hypnotics, anxiolytics and other substances;schizoaffective disorder of the depressed type; adjustment disorder withdepressed mood; and major depressive disorders resulting from a generalmedical condition.
 17. A method for the treatnent of a conditionselected from the group consisting of traumatic pain, traumatic avulsionpain, chronic pain, neuropathic pain, various forms of headache,odontalgia, cancer pain, pain of visceral origin, gastrointestinal pain,nerve entrapment pain, sport's injury pain, dysmennorrhoea, menstrualpain, meningitis, arachnolditis, musculoskelatal pain, low back pain,prolapsed disc, sciatica, angina, enkylosing spondyoiitis, gout, burns,scar pain, itch, and thalamic pain, in a mammal in need thereof, saidmethod comprising administering an effective amount of a compound asclaimed in claim
 1. 18. A method for the treatment of a conditionselected from the group consisting of postoperative pain, brachialplexus, osteo arthritis, rheumatoid arthritis, psoriatic arthritis,post-herpetic neuralgia, trigeminal neuralgia, segmental neuralgia,intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy,diabetic neuropathy, chemotherapy-induced neuropathy, AIDS relatedneuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngealneuralgia, reflex sympathetic dystrophy, phantom limb pain, migraine,acute tension headache, chronic tension headache, temporomandibularpain, maxillary sinus pain, cluster headache, spinal stenosis, and poststroke thalamic pain; in a mammal in need thereof, said methodcomprising administering an effective amount of a compound as claimed inclaim
 1. 19. A method for the treatment of sleep disorders in a mammalin need thereof comprising administering an effective amount of acompound as claimed in claim
 1. 20. A method for the treatment ofcognitive disorders in a mammal in need thereof comprising administeringan effective amount of a compound as claimed in claim
 1. 21. A methodfor the treatment of dependence on a substance selected from the groupconsisting of nicotine, alcohol, caffeine, phencyclidinephencyclidine-like compounds, opiates, benzodiazepines, cocaine,sedative drugs, ipnotic drugs, amphetamines, amphetamine-related drugs,and combinations thereof; in a mammal in need thereof, comprisingadministering an effective amount of a compound as claimed in claim 1.22. A method for the treatment of a condition selected from the groupconsisting of inflammation in asthma, inflammation in influenza,inflammation in chronic bronchitis, inflammation in rheumatoidarthritis, inflammatory diseases of the gastrointestinal tract,inflammatory diseases of the skin, inflammatory diseases of the bladder,and eye and dental inflammation; in a mammal in need thereof, saidmethod comprising administering an effective amount of a compound asclaimed in claim
 1. 23. The method according to claim 22, wherein saidinflammatory diseases of the gastrointestinal tract are selected fromthe group consisting of Crohn's disease, ulcerative colitis,inflammatory bowel disease and non-steroidal anti-inflammatory druginduced damage.
 24. A method for the treatment of an allergic disorderin a mammal in need thereof comprising administering an effective amountof a compound as claimed in claim
 1. 25. A method for the treatment ofirritable bowel syndrome in a mammal in need thereof comprisingadministering an effective amount of a compound as claimed in claim 1.26. A method for the treatment of skin disorders in a mammal in needthereof comprising administering an effective amount of a compound asclaimed in claim
 1. 27. A method for the treatment of vasospasticdiseases in a mammal in need thereof comprising administering aneffective amount of a compound as claimed in claim
 1. 28. A method forthe treatment of cerebral ischeamia in a mammal in need thereofcomprising administering an effective amount of a compound as claimed inclaim
 1. 29. A method for the treatment of fibrosing and collagendiseases in a mammal in need thereof comprising administering aneffective amount of a compound as claimed in claim
 1. 30. A method forthe treatment of disorders related to immune enhancement or suppressionin a mammal in need thereof comprising administering an effective amountof a compound as claimed in claim
 1. 31. The process according to claim9, further comprising one or more of the following steps: ii) isolationof the compound of formula (I) as a pharmaceutically acceptable salt ora solvate thereof; and ii) separation of the compound of formula (I)into enantiomers thereof.
 32. A method for the treatment of a majordepressive disorder in a mammal in need thereof comprising administeringto said mammal an effective amount of a compound of formula (I):

wherein each R independently represents a halogen atom or a C₁₋₄ alkylgroup; R₁ represents a C₁₋₄ alkyl group; R₂ represents hydrogen or aC₁₋₄ alkyl group; R₃ represents hydrogen or C₁₋₄ alkyl group; R₄represents a trifluoromethyl group; R₅ represents hydrogen, a C₁₋₄ alkylgroup or C(O)R₆; R₆ represents C₁₋₄ alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄alkyl) or N(C₁₋₄alkyl)₂; m is zero or an integer from 1 to 3; n is aninteger from 1 to 3; or a pharmaceutically acceptable salt or solvatethereof.
 33. The method according to claim 32, wherein said mammal isman.
 34. The method according to claim 32, wherein said major depressivedisorder is selected from the group consisting of bipolar depression;unipolar depression; single or recurrent major depressive episodes withor without psychotic features, catatonic features, melancholic features,atypical features or postpartum onset; dysthymic disorder with early orlate onset and with or without atypical features, neurotic depressionand social phobia; dementia of the Alzheimer's type, with early or lateonset, with depressed mood; vascular dementia with depressed mood; mooddisorders induced by alcohol, amphetamines, cocaine, hallucinogens,inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics andother substances; and schizoaffective disorder of the depressed type.35. The method according to claim 32, wherein said major depressivedisorder is selected from the group consisting of bipolar depression andunipolar depression.
 36. The method according to claim 32, furthercomprising administering an effective amount of a serotonin reuptakeinhibitor.
 37. The method according to claim 36, wherein said serotoninreuptake inhibitor is selected from the group consisting of fluoxetine,citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertralineand zimeldine.
 38. The method according to claim 32, further comprisingadministering an effective amount of a dopaminergic antidepressant. 39.The method according to claim 38, wherein said dopaminergicantidepressant is selected from the group consisting of buproprion andamineptine.
 40. The method according to claim 32, wherein said compoundof formula (I) is selected from the group consisting of:4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof.
 41. A method forthe treatment of anxiety in a mammal in need thereof comprisingadministering to said mammal an effective amount of a compound offormula (I):

wherein each R independently represents a halogen atom or a C₁₋₄ alkylgroup; R₁ represents a C₁₋₄ alkyl group; R₂ represents hydrogen or aC₁₋₄ alkyl group; R₃ represents hydrogen or C₁₋₄ alkyl group; R₄represents a trifluoromethyl group; R₅ represents hydrogen, a C₁₋₄ alkylgroup or C(O)R₆; R₆ represents C₁₋₄ alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄alkyl) or N(C₁₋₄alkyl)₂; m is zero or an integer from 1 to 3; n is aninteger from 1 to 3; or a pharmaceutically acceptable salt or solvatethereof.
 42. The method according to claim 41, wherein said mammal isman.
 43. The method according to claim 41, further comprisingadministering an effective amount of a serotonin reuptake inhibitor. 44.The method according to claim 43, wherein said serotonin reuptakeinhibitor is selected from the group consisting of fluoxetine,citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertralineand zimeldine.
 45. The method according to claim 41, further comprisingadministering an effective amount of a dopaminergic antidepressant. 46.The method according to claim 45, wherein said dopaminergicantidepressant is selected from the group consisting of buproprion andamineptine.
 47. The method according to claim 41, wherein said compoundof formula (I) is selected from the group consisting of:4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof.
 48. A method forthe treatment of panic disorder in a mammal in need thereof comprisingadministering to said mammal an effective amount of a compound offormula (I):

wherein each R independently represents a halogen atom or a C₁₋₄ alkylgroup; R₁ represents a C₁₋₄ alkyl group; R₂ represents hydrogen or aC₁₋₄ alkyl group; R₃ represents hydrogen or C₁₋₄ alkyl group; R₄represents a trifluoromethyl group; R₅ represents hydrogen, a C₁₋₄ alkylgroup or C(O)R₆; R₆ represents C₁₋₄ alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄alkyl) or N(C₁₋₄alkyl)₂; m is zero or an integer from 1 to 3; n is aninteger from 1 to 3; or a pharmaceutically acceptable salt or solvatethereof.
 49. The method according to claim 48, wherein said mammal isman.
 50. The method according to claim 48, further comprisingadministering an effective amount of a serotonin reuptake inhibitor. 51.The method according to claim 50, wherein said serotonin reuptakeinhibitor is selected from the group consisting of fluoxetine,citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertralineand zimeldine.
 52. The method according to claim 48, further comprisingadministering an effective amount of a dopaminergic antidepressant. 53.The method according to claim 52, wherein said dopaminergicantidepressant is selected from the group consisting of buproprion andamineptine.
 54. The method according to claim 48, wherein said compoundof formula (I) is selected from the group consisting of:4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof.
 55. A method forthe treatment of a gastrointestinal disorder in a mammal in need thereofcomprising administering to said mammal an effective amount of acompound of formula (I):

wherein each R independently represents a halogen atom or a C₁₋₄ alkylgroup; R₁ represents a C₁₋₄ alkyl group; R₂ represents hydrogen or aC₁₋₄ alkyl group; R₃ represents hydrogen or C₁₋₄ alkyl group; R₄represents a trifluoromethyl group; R₅ represents hydrogen, a C₁₋₄ alkylgroup or C(O)R₆; R₆ represents C₁₋₄ alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄alkyl) or N(C₁₋₄alkyl)₂; m is zero or an integer from 1 to 3; n is aninteger from 1 to 3; or a pharmaceutically acceptable salt or solvatethereof.
 56. The method according to claim 55, wherein said mammal isman.
 57. The method according to claim 25, further comprisingadministering an effective amount of a 5HT3 antagonist.
 58. The methodaccording to claim 57, wherein said 5HT3 antagonist is selected from thegroup consisting of ondansetron, granisetron and metoclopramide.
 59. Themethod according to claim 25, wherein said compound of formula (I) isselected from the group consisting of:4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof.
 60. A method forthe treatment of emesis in a mammal in need thereof comprisingadministering to said mammal an effective amount of a compound offormula (I):

wherein each R independently represents a halogen atom or a C₁₋₄ alkylgroup; R₁ represents a C₁₋₄ alkyl group; R₂ represents hydrogen or aC₁₋₄ alkyl group; R₃ represents hydrogen or C₁₋₄ alkyl group; R₄represents a trifluoromethyl group; R₅ represents hydrogen, a C₁₋₄ alkylgroup or C(O)R₆; R₆ represents C₁₋₄ alkyl, C₃₋₇ cycloalkyl, NH(C₁₋₄alkyl) or N(C₁₋₄alkyl)₂; m is zero or an integer from 1 to 3; n is aninteger from 1 to 3; or a pharmaceutically acceptable salt or solvatethereof.
 61. The method according to claim 60, wherein said mammal isman.
 62. The method according to claim 60, wherein said emesis isdelayed emesis.
 63. The method according to claim 60, wherein saidemesis is anticipatory emesis.
 64. The method according to claim 60,wherein said emesis is induced by cancer chemotherapeutic agents. 65.The method according to claim 64, wherein said cancer chemotherapeuticagent is selected from the group consisting of cyclophosphamide,carmustine, lomustine, chlorambucil, dactinomycin, doxorubicin,mitomycin-C, bleomycin, cytarabine, methotrexate, 5-fluorouracil,etoposide, vinblastine, vincristine, cisplatin, dacarbazine,procarbazine and hydroyurea.
 66. The method according to claim 60,wherein said emesis is induced by radiation sickness or radiationtherapy.
 67. The method according to claim 60, wherein said emesis isinduced by pregnancy.
 68. The method according to claim 60, wherein saidemesis is induced by post-operative sickness.
 69. The method accordingto claim 60, wherein said emesis is induced by migraine.
 70. The methodaccording to claim 60, wherein said emesis is induced by opiodanalgesics.
 71. The method according to claim 60, further comprisingadministering an effective amount of a 5HT3 antagonist.
 72. The methodaccording to claim 71, wherein said 5HT3 antagonist is selected from thegroup consisting of ondansetron, granisetron and metoclopramide.
 73. Themethod according to claim 60 further comprising administering aneffective amount of ondansetron.
 74. The method according to claim 60,wherein said compound of formula (I) is selected from the groupconsisting of:4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid, dimethylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylicacid, methylamide;4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof.
 75. Thepharmaceutical composition as claimed in claim 7 further comprising aserotonin reuptake inhibitor selected from the group consisting offluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine,sertraline and zimeldine.
 76. The pharmaceutical composition as claimedin claim 7 further comprising a dopaminergic antidepressant selectedfrom the group consisting of buproprion and amineptine.
 77. Thepharmaceutical composition as claimed in claim 7 further comprising a5HT3 antagonist selected from the group consisting of ondansetron,granisetron and metoclopramide.
 78. The pharmaceutical composition asclaimed in claim 7 further comprising ondansetron.
 79. A method for thetreatment of inflammatory diseases of the bladder in a mammal in needthereof, said method comprising administering an effective amount of acompound as claimed in claim 1.